TY - JOUR
T1 - A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy
AU - Haghighi, Kobra
AU - Kolokathis, Fotis
AU - Gramolini, Anthony O.
AU - Waggoner, Jason R.
AU - Pater, Luke
AU - Lynch, Roy A.
AU - Fan, Guo Chang
AU - Tsiapras, Dimitris
AU - Parekh, Rohan R.
AU - Dorn, Gerald W.
AU - MacLennan, David H.
AU - Kremastinos, Dimitrios Th
AU - Kranias, Evangelia G.
PY - 2006/1/31
Y1 - 2006/1/31
N2 - The sarcoplasmic reticulum Ca2+-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca2+-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca2+-ATPaSe superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca2+-ATPase activity, the nonreversible super-inhibitory function of mutant PLW-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.
AB - The sarcoplasmic reticulum Ca2+-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca2+-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca2+-ATPaSe superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca2+-ATPase activity, the nonreversible super-inhibitory function of mutant PLW-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.
KW - Calcium cycling
KW - Dilated cardiomyopathy
KW - Heart failure
KW - Mutation
KW - Phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=31944450889&partnerID=8YFLogxK
U2 - 10.1073/pnas.0510519103
DO - 10.1073/pnas.0510519103
M3 - Article
C2 - 16432188
AN - SCOPUS:31944450889
VL - 103
SP - 1388
EP - 1393
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 5
ER -